Role of gene therapy in Fanconi anemia: A systematic and literature review with future directions
Hematology/oncology and stem cell therapy. 2021
Gene therapy (GT) has been reported to improve bone marrow function in individuals with Fanconi anemia (FA); however, its clinical application is still in the initial stages. We conducted this systematic review, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to assess the long-term safety and clinical outcomes of GT in FA patients. Electronic searches from PubMed, Web of Science, Cochrane Library, and Google Scholar were conducted and full texts of articles meeting our inclusion criteria were reviewed. Three clinical trials were included, with a total of nine patients and mean age of 10.7 ± 5.7 years. All patients had lentiviral-mediated GT. A 1-year follow-up showed stabilization in blood lineages, without any serious adverse effects from GT. A metaregression analysis could not be conducted, as very little long-term follow-up data of patients was observed, and the median survival rate could not be calculated. Thus, we can conclude that GT seems to be a safe procedure in FA; however, further research needs to be conducted on the longitudinal clinical effects of GT in FA, for a better insight into its potential to become a standard form of treatment.
Metabolomics-Based Clinical Efficacy of Compound Shenlu Granule, a Chinese Patent Medicine, in the Supportive Management of Aplastic Anemia Patients: A Randomized Controlled Pilot Trial
Evidence-based complementary and alternative medicine : eCAM. 2021;2021:6655848
OBJECTIVE To explore the clinical efficacy and mechanism of compound Shenlu granule (SLG) treatment in patients with aplastic anemia (AA). METHODS A total of 89 AA patients were randomly divided into an SLG supportive group (group A, n = 44) and a control group (group B, n = 45) while continuing Western medical management. After 6 months, hemograms, traditional Chinese medicine (TCM) syndrome scores, and overall clinical efficacy rate were assessed. Serum metabolomics characteristics were observed using ultraperformance liquid chromatography-mass spectrometry after SLG intervention. RESULTS The levels of red blood cell (RBC), hemoglobin (Hb), and platelet (PLT) were increased in both groups after treatment for 6 months (P < 0.05), and in group A, the elevation of PLT became much more significant (P < 0.01). The TCM syndrome score was lower in group A than in group B after treatment (P < 0.05). Metabolomics data showed a significant difference in the patients using SLG after 6 months, and 14 biomarkers were identified. CONCLUSION SLG supportive treatment showed positive results in patients with AA, and metabolomics data indicated that SLG influenced aminoacyl-tRNA biosynthesis and glycerophospholipid metabolism to gradually return to normal.
Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants
The Cochrane database of systematic reviews. 2020;2:Cd004865
BACKGROUND Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia. OBJECTIVES To assess the effectiveness and safety of early versus late initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight (LBW) infants. SEARCH METHODS The standard search of the Cochrane Neonatal Review Group (CNRG) was performed in 2006 and updated in 2009. Updated search in September 2009 as follows: The Cochrane Library, MEDLINE (search via PubMed), CINAHL and EMBASE were searched from 2005 to September 2009. The searches were repeated in March 2012. The Pediatric Academic Societies' Annual meetings were searched electronically from 2000 to 2012 at Abstracts2View(TM) as were clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp). SELECTION CRITERIA Randomised or quasi-randomised controlled trials enrolling preterm or LBW infants less than eight days of age. INTERVENTION Early initiation of EPO (initiated at less than eight days of age) versus late initiation of EPO (initiated at eight to 28 days of age). DATA COLLECTION AND ANALYSIS The standard methods of the CNRG were followed. Weighted treatment effects included typical risk ratio (RR), typical risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and mean difference (MD), all with 95% confidence intervals (CI). A fixed-effect model was used for meta-analyses and heterogeneity was evaluated using the I-squared (I(2)) test. MAIN RESULTS No new trials were identified in March of 2012. Two high quality randomised double-blind controlled studies enrolling 262 infants were identified. A non-significant reduction in the 'Use of one or more RBC transfusions' [two studies 262 infants; typical RR 0.91 (95% CI 0.78 to 1.06); typical RD -0.07 (95% CI -0.18 to 0.04; I(2) = 0% for both RR and RD] favouring early EPO was noted. Early EPO administration resulted in a non-significant reduction in the "number of transfusions per infant" compared with late EPO [typical MD - 0.32 (95% CI -0.92 to 0.29)]. There was no significant reduction in total volume of blood transfused per infant or in the number of donors to whom the infant was exposed. Early EPO led to a significant increase in the risk of retinopathy of prematurity (ROP) (all stages) [two studies, 191 infants; typical RR 1.40 (95% CI 1.05 to 1.86); typical RD 0.16 (95% CI 0.03 to 0.29); NNTH 6 (95% CI 3 to 33)]. There was high heterogeneity for this outcome (I(2) = 86% for RR and 81% for RD). Both studies (191 infants) reported on ROP stage > 3. No statistically significant increase in risk was noted [typical RR 1.56 (95% CI 0.71 to 3.41); typical RD 0.05 (-0.04 to 0.14)] There was no heterogeneity for this outcome (0% for both RR and RD). No other important favourable or adverse neonatal outcomes or side effects were reported. AUTHORS' CONCLUSIONS The use of early EPO did not significantly reduce the 'Use of one or more RBC transfusions' or the 'Number of transfusions per infant" compared with late EPO administration. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage > 3 with early EPO treatment is of great concern.
The role of Lactobacillus reuteri DSM 17938 for the absorption of iron preparations in children with iron deficiency anemia
Korean journal of pediatrics. 2019;62(5):173-178
PURPOSE To determine whether Lactobacillus reuteri DSM 17938 plays a role in absorption of iron preparations given to children with iron deficiency anemia (IDA). METHODS We performed a quasi-experimental study involving pre- and postintervention tests using a control group in North Sulawesi province, Indonesia, between July and September 2017. We conducted a single-blind controlled trial that included primary school children who were diagnosed with IDA based on reticulocyte hemoglobin equivalent (Ret-He) levels <27.8 pg/L. RESULTS A total of 66 children were randomized into 2 groups. Thirty-four children received iron preparations with the addition of L. reuteri DSM 17938 (group 1), whereas the other 32 received iron preparations alone (group 2). The baseline Ret-He levels before intervention were similar in both groups. After 14 days of intervention, mean Ret-He level in group 1 changed from 24.43+/-1.64 to 28.21+/-1.72 pg/ L (P=0.000). Mean Ret-He level in group 2 changed from 24.31+/-1.42 to 27.03+/-2.14 pg/L (P=0.000). Statistical analysis showed a significant increase in Ret-He levels in both groups; Ret-He levels were significantly higher in the experimental group than in the control group (P<0.05). CONCLUSION Children with IDA receiving iron preparations with L. reuteri DSM 17938 for 14 days show higher Ret-He levels than those receiving iron preparations alone.
Diamond Blackfan Anemia: Genetics, Pathogenesis, Diagnosis and Treatment
Diamond Blackfan Anaemia (DBA) is a sporadic inherited anemia with broad spectrum of anomalies that are presented soon after delivery. It is inherited mainly in autosomal dominant inheritance manner and caused by mutations and deletions in either large or small ribosomal protein genes that results in an imbalance between the biosynthesis of rRNA and ribosomal proteins, eventually the activation and stabilization of p53. Diagnosing DBA is usually problematic due to a partial phenotype and its wide inconsistency in its clinical expression; however, molecular studies have identified a heterozygous mutated gene in up to 50% of the DBA cases and corticosteroid drugs are the backbone treatment options of DBA. Anomalies in bone marrow function in DBA cases are broadly associated with both congenital and acquired bone marrow failure syndromes in human. In this review different literatures were searched in Medline (eg. PubMed, PMC, Hinari, Google scholar), OMIM, EMBASE by using search engines (Google, Yahoo, Baidu Ask.com) and searching was performed by using search key words (DBA, ribosomopathies, Bone Marrow Failure Syndromes, pure red cell aplasia). Only human studies were included. This review is summarizing the current understandings of DBA.
A prospective, multicenter, randomized comparison of iron isomaltoside 1000 versus iron sucrose in patients with iron deficiency anemia (the FERWON-IDA trial)
American journal of hematology. 2019
Iron deficiency anemia (IDA) is prevalent and intravenous iron, especially if given in a single dose, may result in better adherence compared with oral iron. The present trial (FERWON-IDA) is part of the FERWON program with iron isomaltoside 1000/ferric derisomaltose (IIM) evaluating safety and efficacy of high dose IIM in IDA patients of mixed etiologies. This was a randomized, open-label, comparative, multi-center trial conducted in the USA. IDA patients were randomized 2:1 to a single dose of 1000 mg IIM or iron sucrose (IS) administered as 200 mg intravenous injections up to five times. The co-primary endpoints were adjudicated serious or severe hypersensitivity reactions and change in hemoglobin from baseline to week eight. 1512 patients were enrolled. The frequency of patients with serious or severe hypersensitivity reactions was 0.3% (95% confidence interval: 0.06;0.88) versus 0.4% (0.05;1.45) in the IIM and IS group, respectively. The co-primary safety objective was met and no risk difference was observed between groups. The co-primary efficacy endpoint of non-inferiority in hemoglobin change was met, and IIM led to a significantly more rapid hematological response in the first two weeks. The frequency of cardiovascular events was 0.8% and 1.2% in the IIM and IS group, respectively (p=0.570). The frequency of hypophosphatemia was low in both groups. IIM administered as 1000 mg resulted in a more rapid and more pronounced hematological response compared with IS which required multiple visits. The safety profile was similar with a low frequency of hypersensitivity reactions and cardiovascular events. This article is protected by copyright. All rights reserved.
Effect of Hemocare Syrup and Hemocare XT Tablets on Hemoglobin levels in iron deficiency anemia among women of reproductive age: A randomized, placebo controlled, open label trial
Contemporary clinical trials communications. 2019;15:100425
Background: Iron deficiency anemia is one of the important public health problems in developing countries among the women of reproductive age group. Hemocare formulation plays a significant role in Iron deficiency anemia because of its Iron content. The present study aimed to investigate the effect of Hemocare Syrup and Hemocare XT Tablets compared with placebo on Hemoglobin Levels in Iron Deficiency Anemia among Women of Reproductive Age. Methods: A prospective, interventional, randomized, open label, placebo controlled trial has been conducted with 126 patients. Eligible patients randomly received either Placebo 100mg or Hemocare XT Tablet 100mg or 10ml of Hemocare Syrup once daily in the same manner for 4 weeks. Hemoglobin values were documented at the end of 15th day, 21st day and 30th day. Results: The baseline hemoglobin values were compared with each follow up and statistically significant difference was found at the end of 30th day of Hemocare Syrup and Hemocare XT treatment (P<0.05) but there was no significant difference observed in the placebo group. The study results revealed that 30 days treatment of Hemocare Syrup and Hemocare XT Tablets increases the Hemoglobin levels to 12.46+/-0.44g/dl and 12.90+/-0.98g/dl from 9.08+/-2.54g/dl and 9.68+/-2.04g/dl respectively. Conclusion: Hemocare Syrup and Hemocare XT Tablets treatment showed clinically significant improvement in hemoglobin levels from the baseline and placebo group.
The Efficacy of Ferumoxytol for Iron Deficiency Anemia: A Meta-Analysis of Randomized Controlled Trials
Acta haematologica. 2019;:1-7
INTRODUCTION This systematic review and meta-analysis aims to explore the influence of ferumoxytol versus placebo on iron deficiency anemia. METHODS We search for randomized controlled trials (RCTs) assessing the effect of ferumoxytol on iron deficiency anemia on PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases. This meta-analysis is performed using the random-effects model. RESULTS Four RCTs are included in the meta-analysis. Compared with the control group for iron deficiency anemia, intravenous ferumoxytol can significantly improve the proportion of patients with a ≥20 g/L hemoglobin (Hb) increase (RR = 18.43; 95% CI = 7.29-46.57; p < 0.00001), the proportion of patients with an Hb level ≥120 g/L (RR = 18.55; 95% CI = 8.66-39.72; p < 0.00001), transferrin saturation (mean difference = 11.08; 95% CI = 9.86-12.31; p < 0.00001) and FACIT-fatigue score (mean difference = 4.60; 95% CI = 3.21-6.00; p < 0.00001), but has no remarkable influence on adverse events (RR = 1.33; 95% CI = 0.84-2.10; p = 0.22), serious adverse events (RR = 1.22; 95% CI = 0.74-2.02; p = 0.44), and death (RR = 0.32; 95% CI = 0.05-1.95; p = 0.22). CONCLUSIONS Intravenous ferumoxytol can provide the important benefits for iron deficiency anemia.
Title: Is Iron Supplementation Influenced by Sub-Clinical Inflammation?: A Randomized Controlled Trial Among Adolescent Schoolgirls in Myanmar
Iron absorption was impaired in the presence of sub-clinical inflammation (SCI) and might hamper the effect of iron supplementation. The purpose of the study was to identify the influence of SCI on iron supplementation. A randomized, double-blinded, placebo-controlled experimental study was conducted among anaemic adolescent schoolgirls in Ayeyarwady region, Myanmar. A total of 402 schoolgirls were recruited from six schools screened from 1269 girls who were assigned into one of four groups: Folate group (2.5 mg of folate), Vitamin A group (15,000 IU of vitamin), Iron folate group (60 mg elemental iron and folate) and Iron, and vitamin A and folate group. Supplementation was done once a week for 12 weeks. Iron, vitamin A and inflammation were measured at the baseline, middle and endline. Changes in serum ferritin and body iron were significantly higher in the IFA and IFA + vitA among those without SCI. There was interaction between vitamin A and SCI on Hb changes. Analysis of GLM repeated measure showed interactions between treatment and SCI for hemoglobin and serum transferrin receptor. Those treated with vitamin A had better outcomes when there was SCI. Inflammation accompanied a negative effect on iron supplementation and vitamin A improved efficacy of iron supplementation in the presence of SCI.
Hepcidin-guided screen-and-treat interventions against iron-deficiency anaemia in pregnancy: a randomised controlled trial in The Gambia
The Lancet. Global health. 2019;7(11):e1564-e1574
BACKGROUND WHO recommends daily iron supplementation for pregnant women, but adherence is poor because of side-effects, effectiveness is low, and there are concerns about possible harm. The iron-regulatory hormone hepcidin can signal when an individual is ready-and-safe to receive iron. We tested whether a hepcidin-guided screen-and-treat approach to combat iron-deficiency anaemia could achieve equivalent efficacy to universal administration, but with lower exposure to iron. METHODS We did a three-arm, randomised, double-blind, non-inferiority trial in 19 rural communities in the Jarra West and Kiang East districts of The Gambia. Eligible participants were pregnant women aged 18-45 years at between 14 weeks and 22 weeks of gestation. We randomly allocated women to either WHO's recommended regimen (ie, a daily UN University, UNICEF, and WHO international multiple-micronutrient preparation [UNIMMAP] containing 60 mg iron), a 60 mg screen-and-treat approach (ie, daily UNIMMAP containing 60 mg iron for 7 days if weekly hepcidin was <2.5 mug/L or UNIMMAP without iron if hepcidin was ≥2.5 mug/L), or a 30 mg screen-and-treat approach (ie, daily UNIMMAP containing 30 mg iron for 7 days if weekly hepcidin was <2.5 mug/L or UNIMMAP without iron if hepcidin was ≥2.5 mug/L). We used a block design stratified by amount of haemoglobin at enrolment (above and below the median amount of haemoglobin on every enrolment day) and stage of gestation (14-18 weeks vs 19-22 weeks). Participants and investigators were unaware of the random allocation. The primary outcome was the amount of haemoglobin at day 84 and was measured as the difference in haemoglobin in each screen-and-treat group compared with WHO's recommended regimen; the non-inferiority margin was set at -5.0 g/L. The primary outcome was assessed in the per-protocol population, which comprised all women who completed the study. This trial is registered with the ISRCTN registry, number ISRCTN21955180. FINDINGS Between June 16, 2014, and March 3, 2016, 498 participants were randomised, of whom 167 were allocated to WHO's recommended regimen, 166 were allocated to the 60 mg per day screen-and-treat approach, and 165 were allocated to the 30 mg per day screen-and-treat approach. 78 participants were withdrawn or lost to follow-up during the study; thus, the per-protocol population comprised 140 women assigned to WHO's recommended regimen, 133 allocated to the 60 mg screen-and-treat approach, and 147 allocated to the 30 mg screen-and-treat approach. The screen-and-treat approaches did not exceed the non-inferiority margin. Compared with WHO's recommended regimen, the difference in the amount of haemoglobin at day 84 was -2.2 g/L (95% CI -4.6 to 0.1) with the 60 mg screen-and-treat approach and -2.7 g/L (-5.0 to -0.5) with the 30 mg screen-and-treat approach. Adherence, reported side-effects, and adverse events were similar between the three groups. The most frequent side-effect was stomachache, which was similar in the 60 mg screen-and-treat group (82 cases per 1906 person-weeks) and with WHO's recommended regimen (81 cases per 1974 person-weeks; effect 1.0, 95% CI 0.7 to 1.6); in the 30 mg screen-and-treat group the frequency of stomachache was slightly lower than with WHO's recommended regimen (58 cases per 2009 person-weeks; effect 0.7, 95% CI 0.5 to 1.1). No participants died during the study. INTERPRETATION The hepcidin-guided screen-and-treat approaches had no advantages over WHO's recommended regimen in terms of adherence, side-effects, or safety outcomes. Our results suggest that the current WHO policy for iron administration to pregnant women should remain unchanged while more effective approaches continue to be sought. FUNDING Bill & Melinda Gates Foundation and the UK Medical Research Council.
Pregnant women aged 18-45 years at between 14 weeks and 22 weeks of gestation (n=498).
WHO recommended regimen [UNIMMAP] containing 60 mg iron, (n=140).
A 60 mg screen-and-treat approach (daily UNIMMAP containing 60 mg iron for 7 days if weekly hepcidin was <2.5 mug/L or UNIMMAP without iron if hepcidin was >/=2.5 mug/L), (n=133). Or a 30 mg screen-and-treat approach (daily UNIMMAP containing 30 mg iron for 7 days if weekly hepcidin was <2.5 mug/L or UNIMMAP without iron if hepcidin was >/=2.5 mug/L), (n= 147).
Compared with WHO's recommended regimen, the difference in the amount of haemoglobin at day 84 was -2.2 g/L with the 60 mg screen-and-treat approach and -2.7 g/L with the 30 mg screen-and-treat approach. Adherence, reported side-effects, and adverse events were similar between the three groups. The most frequent side-effect was stomachache, which was similar in the 60 mg screen-and-treat group (82 cases per 1906 person-weeks) and with WHO's recommended regimen (81 cases per 1974 person-weeks; effect 1.0); in the 30 mg screen-and-treat group the frequency of stomachache was slightly lower than with WHO's recommended regimen (58 cases per 2009 person-weeks; effect 0.7).